Genomic analyses identify molecular subtypes of pancreatic cancer

Abstract

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

Concepts to Target MYC in Pancreatic Cancer

“…The squamous subtype of the disease, which overlaps with the quasi-mesenchymal subtype defined by Collisson and colleagues (21), is characterized by an activated MYC pathway (20) and the poorest outcome (20)(21)(22). These observations moreover reinforce MYC being a relevant driver in PDAC and argue that MYC targeting strategies are needed.…”

“…Here, Bailey and colleagues demonstrated the existence of four subtypes of PDAC: (i) the squamous subtype, (ii) the pancreatic progenitor subtype, (iii) the immunogenic subtype, and (iv) the aberrantly differentiated endocrine exocrine subtype (20). The squamous subtype of the disease, which overlaps with the quasi-mesenchymal subtype defined by Collisson and colleagues (21), is characterized by an activated MYC pathway (20) and the poorest outcome (20)(21)(22).…”

Epigenetics of gastrointestinal diseases: notes from a workshop

“…Attempts have been made to identify subtypes of PDAC in hopes of developing more specific and effective therapies for use within subtypes [32–34]. Thus far, genome-wide studies of gene mutations in PDAC have not led to selective treatments of PDAC subtypes based on mutation type.…”

Genomic Heterogeneity: Next-Generation Sequencing Enables Biomarker Identification for Hepatocellular Carcinoma

“…Bailey et al [18] have performed a comprehensive genomic analysis of 456 pancreatic ductal adenocarcinoma patients. Whole-genome sequencing was performed on 179 and WES on 204 tumor samples.…”